The idea behind this chapter doesn’t really need words that are poetic, personal, colourful or clever because it is explosive enough said plain and simple: our variable immune system genes influence whether or not pregnancy is successful. Couples having certain combinations of immune-system genes are more likely to miscarry or have other problems in pregnancy. This extends the reach of compatibility genes into a whole other realm of human biology and links two of the most powerful natural forces that control human existence – survival from disease and successful reproduction.
Pregnancy has long been recognized as a problem for the immune system. Peter Medawar is often credited with bringing the issue into focus in an influential article published in 1953.1 From his experiments – and the theories of his contemporary Burnet – he knew that detection of non-self can trigger an immune reaction, and this is what causes transplant rejection. Medawar realized that a foetus has half its genes from its father – so why doesn’t the mother’s immune system attack the foetus for being different, just like in a transplant? Every baby in every mother’s womb must survive against the normal rules for successful transplantation. And so – Medawar reasoned – pregnancy presents a paradox, because a mother must nourish, not reject, tissue that is genetically different from her own.
Medawar considered that the most likely solution to this paradox is an anatomical separation of the foetus from its mother, but he never made much headway into exploring any details.2 He was right that there is no direct contact between an embryo and its mother: a baby develops within an amniotic sac, and its blood circulation is kept separate from the mother’s. The place where genetically different cells derived from the foetus could meet the mother’s immune system is in the placenta, the organ which grows for nine months to connect the developing baby and the mother through the umbilical cord. The placenta is where an immune reaction must be prevented – and where the answer to Medawar’s paradox must lie.
The human placenta lies on one side of the mother’s uterus (or womb) and its main job is to allow nutrients and gases to pass between the mother and baby. The structure of the placenta – and birth in general – varies a lot between animals. While this is a great source of wonder for anyone fascinated by the diversity of life on earth, these differences are a source of frustration for scientists trying to work out basic principles of pregnancy. This is one area of human biology for which studies in animals are of limited use.3 But, unlike most other human organs, it’s relatively easy to obtain a human placenta, and so we know a great deal about the cells that go to make the placenta and its overall anatomy.
In the human placenta, maternal blood flows over a tree of finger-like projections, or villi, made from cells derived from the foetus. These villi contain foetal blood – to collect gases and nutrients – and are coated on the outside with cells that are called trophoblast cells. These trophoblast cells are, in effect, foetal cells that are in direct contact with the mother. A second type of cell from the foetus also contacts the mother’s tissue – they are called extra-villous trophoblast cells. These foetal cells directly invade the mother’s uterus and affect the walls of her arteries to help make sure that there is blood flow sufficient enough for nutrients to be absorbed by the foetus.4 Where these trophoblast and extra-villous trophoblast cells from the embryo contact the mother, two individuals are connected in the most intimate way possible.
From this, the answer to Medawar’s paradox is reduced to understanding trophoblast cells. A solution to the problem would be if trophoblast cells come into contact with the mother’s blood but not her immune cells. That is, if the mother’s immune cells are prevented from entering the uterus during pregnancy, making the uterus a privileged site in the body like the eye and the testis – special places where immune responses are prevented from occurring. Rupert Billingham – from Medawar’s holy trinity – was one prominent scientist who explored this idea during the 1960s. But he found out, as did others, that immune cells can reach the uterus during pregnancy and infections can be fought there.5 This isn’t the answer.
Part of the true solution to Medawar’s paradox is that trophoblast cells derived from the foetus are different from almost all other types of cell in that they are not able to trigger a strong immune response. Specifically, trophoblast cells don’t make the proteins HLA-A and HLA-B, while almost all other types of cell in the body do. Trophoblast cells still make the HLA-C protein,6 but by lacking HLA-A or HLA-B, there’s not much for the mother’s T cells to look at on trophoblast cells. In this way, they can avoid switching on the mother’s T cells.
The situation is reminiscent of how some viruses infect cells and interfere with HLA proteins so that T cells can’t detect that anything’s wrong. But when that happens, another arm of your immune system spots the problem. Recall how Natural Killer (NK) cells can be activated by detecting ‘missing self’; a loss of HLA proteins at the surface of cells can itself be taken as a sign of trouble. So if trophoblast cells inherently lack HLA proteins to avoid an immune reaction from the mother’s T cells, why wouldn’t they instead activate the mother’s NK cells?
One solution to this conundrum would be if a mother’s NK cells don’t enter her uterus during pregnancy, even if other immune cells do. And so this begs the question of which kinds of immune cells there are in the uterus. Three pioneering British women answered this question independently in the late 1980s. One was Ashley Moffett, working at the time with Malaysian-born Yung Wai (Charlie) Loke at the University of Cambridge.7 Loke was already in his fifties while Moffett was not yet an established scientist, having focused her career instead on clinical medicine. Loke and Moffett’s story – a long partnership which began with Moffett’s observations about which type of immune cells are present in the uterus – leads us to the unexpected link between the immune system and pregnancy.
Born in 1934, Loke had taught medicine in Malaysia before being recruited to Cambridge in 1967, where he had earlier been a student and where he then stayed thirty-five years, until retiring in 2002. His reputation was established in 1986, by being the first to isolate trophoblast cells from a human placenta so that they could be studied in detail. Moffett says that Loke is just as happy ‘in a sarong, a tweed jacket or his scarlet academic gown’.8
Loke had had a distant relationship with his parents and was looked after by nannies during his early childhood. From age thirteen, he went to boarding school in the UK. He had wanted to be a marine biologist but ended up in medicine because he was taught at boarding school that medicine – unlike marine biology – was a proper career. Also at boarding school, he was given his name – Charlie – because nobody could pronounce Yung Wai. He has always remained an outsider. Even though he spent so long in Cambridge, he would often feel excluded when a conversation centred on an aspect of society he didn’t know much about, sometimes bringing on a deep loneliness in the company of friends and colleagues.9
Before being sent to boarding school in the UK, Loke and his family fled from Malaysia to Singapore when it was captured by the Japanese in 1941. He moved again and lived under Japanese occupation in Kuala Lumpur with scarce resources and a diet of brown rice.10 Memories of people being moved against their will influenced him ever after. He would always refrain from joining organized sightseeing tours often arranged during a scientific congress because he didn’t like the idea of being shepherded about in a large group against one’s free will.11 His passion for freedom included making sure that his thinking was never trapped in paradigm.12
In fact, Loke was about as free as any scientist could be. He came from an exceptionally wealthy family, his grandfather having founded the tin and rubber industries in Malaysia. So, if he didn’t get a particular research project funded through the normal peer-review system, he could just fund the work himself.13
At the time they began to work together, Moffett had only recently returned to work after a five-year career break during which time she had three children.14 She had first met Loke while she was an undergraduate student; Moffett being one of about twenty women studying medicine with nearly 250 men.15 Moffett had trained as a neurologist but took a job as the pathologist in a Cambridge maternity hospital, simply because it was all that was available. Quickly, she realized that a maternity hospital is a hectic environment to work in: babies are born round the clock without any consideration for sociable working hours. Her duty was to diagnose problems in pregnancy from biopsies and medical notes, but when Moffett queried how the biopsies actually related to the underlying causes of problems in pregnancy, nobody seemed to know; nobody had time to think about it. Biopsies could provide tell-tale signatures of particular problems in pregnancy, but nobody knew what caused such characteristics.
Moffett was often half asleep – with babies on her mind at work and at home – but she wanted to understand what happens when pregnancies didn’t work out, and pre-eclampsia was one problem she came across frequently. It is a condition caused by abnormalities in implantation, resulting in poor blood flow in the placenta and high blood pressure in the mother. Left unchecked, it can lead to eclampsia, with symptoms that include seizures and coma – and which can be fatal. Looking through the biopsies, Moffett couldn’t help but wonder why some women have this problem and others don’t. And it felt unfair to her that other medical problems were studied so much more intensely. She felt that there was a gravitas given to, say, research in cancer – even relatively rare cancers – that just didn’t seem to apply to studying pre-eclampsia, even though it affects 6–8 per cent of pregnancies. Pre-eclampsia can often be resolved with speedy delivery of the baby by caesarean section or induction of birth, but occasionally an abortion is necessary. The intervention saves lives, but premature birth of babies can sometimes lead to other problems – and the root cause of the problem is left unchecked. Moffett felt that if pre-eclampsia was a male problem, it wouldn’t have been so under-studied.16
Each time she brought her microscope into focus, she didn’t just seek a diagnosis, she looked for clues as to what caused pre-eclampsia. One thing she noticed over the slides she examined was that immune cells in the uterus were often particularly speckled or granular. Other scientists had already found immune cells present where foetal trophoblast cells invade a mother’s uterus, but their identity was unclear. Moffett had read that an unusually speckled appearance was characteristic of NK cells – recall that this was the trait used to identify human NK cells in the first place. In 1987, she decided to go and see Loke, the renowned local expert in the placenta – to tell him that she had discovered a lot of NK cells present in the uterus during pregnancy. She expected the old master to be flabbergasted – but his response was simply: what are NK cells?17
Loke wasn’t ignorant. Rather it was a time when NK cells were relatively little known. Kärre’s idea for the way in which NK cells detect diseased cells – the ‘missing self’ hypothesis – was only beginning to be debated. Loke got up to speed on NK cells and he invited Moffett to leave her hospital work and take up research full time in his laboratory. He mentioned that, if she really proved that NK cells are abundant in the uterus, she would probably never return to patient care. Moffett agreed to take a short sabbatical in 1987 and Loke’s prediction proved right; she never did return to clinical medicine.
In Loke’s lab, Moffett examined the uterine immune cells by systematically comparing stains for different kinds of cell and confirmed that a huge fraction of them were NK cells. They published their observations in a relatively obscure specialist journal.18 Neither Loke nor Moffett was ambitious in a career-focused way and they never thought it important to seek a higher-profile place to publish.19 The two others who discovered the presence of NK cells in the mother’s uterus around the same time as Moffett were Judith Bulmer at Newcastle University and Phyllis Starkey at the University of Oxford.20 Bulmer works as a clinical consultant for placental pathology, while Starkey left science to pursue a career in politics, becoming a Labour Member of Parliament in 1997 – it gave her ‘a chance to change people’s lives for the better’.21 It probably helped her in politics that she had training in science like it helps in science to be good at politics.
It isn’t just coincidence that much of the research described earlier in this book was male-dominated, while here women take the lead. In the six decades over which this story has unravelled, the role of women in science has improved considerably – a trend likely to continue as the stereotype of the male scientist becomes outdated and ignored. All three women, however, published their discovery about the placenta in specialist journals which weren’t read by the mainstream NK-cell research community. The first time NK-cell researchers heard of this discovery was when Moffett presented her data in a poster at the NK-cell congress held in St Petersburg, Florida, in 1992. Discussion at that meeting centred on how NK cells detect diseased cells – and Kärre’s idea of NK cells looking for ‘missing self’ was beginning to be accepted. All research on human NK cells at that time was done using cells isolated from blood. Moffett’s suggestion that NK cells were also abundant in the uterus was met with bemusement. At that time, these meetings were male-dominated, and by far the most common question asked about her discovery was simply: ‘What is a uterus?’22
Nowadays, the presence of so many NK cells is known to be a characteristic change to the uterus caused by the hormone progesterone. NK cells accumulate as part of the monthly cyclical changes that occur in the uterus and they die off a couple of days before menstruation, or stay if pregnancy occurs. Rather than ‘What is a uterus?’, the important question to be asked is ‘What are all these NK cells doing there?’ NK cells specialize in detecting a loss of compatibility protein from cells, which is exactly the case for trophoblast cells – so what stops these NK cells from attacking these cells in the placenta?
There’s one very special thing about trophoblast cells which looks to be important for resolving this: although they lack HLA-A and -B, they have at their surface a peculiar HLA protein that’s almost never seen anywhere else in the body: HLA-G. The shape of HLA-G is very similar to the -A, -B, and -C proteins, but HLA-G differs from these other HLA proteins in that it doesn’t vary much between each of us (it’s one of the non-classical HLA proteins).23
The HLA-G gene was identified in the late 1980s, but it took many years to find out where it was used in the body.24 Early evidence for the protein being used in the placenta sparked controversy – due to different views as to what constitutes proof of the presence of HLA-G. The problem is that there’s such huge variability in HLA-A, -B and -C proteins that it is very difficult to get any reagent or process to reveal the presence of HLA-G specifically and not any other HLA protein.25 Eventually, a consensus was reached that HLA-G is indeed on placental trophoblast cells, and so the next question was: what does it do there?
Several of its features indicated that it would not do the same job as the other, more common, HLA proteins. For example, HLA-G stays at the surface of cells for a very long time, while other HLA proteins turn over to give an up-to-date report on what’s being made inside each cell.26 From 1995, attention focused on whether or not HLA-G on trophoblast cells would affect the NK cells that Bulmer, Moffett and Starkey had found to be abundant in the uterus during pregnancy. In 1996, several teams independently found that HLA-G was capable of switching off the killing action of NK cells.27 The implication was that HLA-G on trophoblast cells marks these cells as special – specifically telling the mother’s NK cells to leave these cells alone; these foetal cells are non-self but they are not dangerous. For such an important discovery, repetition of the experiment in different labs is needed to build confidence in the community, so it helped that different teams observed NK cells being switched off by HLA-G. But in fact, the teams disagreed over the way in which HLA-G did it. Researchers were at odds over how NK cells were able to detect the presence of HLA-G or, specifically, which receptors on NK cells could bind to HLA-G.
One possible cause of discrepancy was that each team was using their own lab’s cells genetically altered to make HLA-G. To test whether or not this was a problem, one group requested a sample of the cells being used in another lab so that it could carry out a direct comparison. The request alone is enough to spark some feeling of ill trust, but things got far worse when the wrong cells were sent out. Somewhere along the line, one team’s cells had been mixed up, so that, in fact, experiments thought to be done on cells having HLA-G had actually used cells genetically altered to make a different HLA protein instead. Not to name or shame any particular person or team, this anecdote shows how science progresses through everyday human errors, which in fact occur far more frequently than strokes of genius or even serendipitous breakthroughs.
In the end, it became clear that some of the data that had been published were plain wrong. No one’s publications were ever formally retracted, or even officially corrected; just everyone in the community knew where the errors were. We know now that HLA-G can switch off immune cells in several ways, but it still remains unclear whether it affects all NK cells or only a fraction of them.28 In any case, Moffett – and many others – think that the whole idea of it being critically important to switch off uterine NK cells has been one big red herring, a decade-long diversion because our thinking took a wrong turn.
As we’ve just discussed, it does seem to make sense that trophoblast cells – which lack normal HLA proteins – have the special HLA-G protein to switch off NK cells that would otherwise kill cells that are missing HLA proteins. Well, sort of – it still seems strange that so many NK cells are present in the uterus during pregnancy. They surely can’t be there just to be turned off?
Moffett thinks that Medawar’s question of how a mother’s immune system gets switched off might have been the wrong thing to ask all along. Instead – Moffett thinks – we should be questioning why immune cells accumulate at the foetal–maternal interface in the first place. She’s right; because a closer look at these uterine NK cells shows us that these cells aren’t what they seemed at first.
NK cells from blood take their name – Natural Killers – for being good at killing diseased cells such as tumours, but it turns out that NK cells from the uterus are only weakly able to kill other cells. In fact, this was something Moffett reported early on but the observation was largely ignored for well over a decade. Everyone raced to work out how uterine NK cells were switched off without carefully considering whether or not they really need to be switched off.
Eventually, others caught up with Moffett. Several research teams – including Jack Strominger at Harvard, who had earlier worked with Bjorkman and Wiley to get the shape of the HLA protein – also found out that uterine NK cells were not good at killing.29 In fact, Strominger established that the activity of hundreds of genes is different in uterine NK cells compared to blood NK cells.30 The uterine cells get to keep the name ‘Natural Killer’ because they share many features with their blood counterparts – and they can deliver a lethal hit if pushed – but they don’t seem to have a killer instinct. It may not be so important after all for trophoblast cells to use HLA-G as protection against NK cells in the uterus, because these immune cells can’t kill very well anyway. And if killing isn’t their thing, what do the NK cells in the placenta really do?
Yaqub (Jacob) Hanna, a Palestinian Arab working with Ofer Mandelboim, an Israeli Jew, both at the Hebrew University in Jerusalem, discovered that NK cells – far from being involved in combat – actually secrete growth factors and other proteins which stimulate the invasion of trophoblast cells into the mother’s uterus. The implication of this is that, far from killing other cells, NK cells in the uterus can help shape the structure of the placenta during early pregnancy.31 Other researchers found that uterine NK cells also have a constructive role in mice (despite there being many differences between pregnancy in mice and that in people).32 One study, for example, even found that a bone-marrow transplant – which provides an abundance of immune cells – can reverse certain reproductive problems in mice.33 So, instead of being agents of destruction, NK cells in the uterus might actually aid blood flow in the placenta and help pregnancy succeed.34
This idea remains open to debate because it’s very hard to test directly what NK cells really do inside a woman’s uterus – and because uterine NK cells are hard to obtain in large numbers. Hanna and Mandelboim’s study, for example, had to use tissue from more than 550 elective abortions.35 To increase the numbers of uterine NK cells, scientists can culture them in the lab before beginning experiments. Some of the cell’s properties could very well change when grown in the lab, and they may well behave differently from when they are in a uterus. But there is evidence that Hanna and Mandelboim’s findings are relevant to NK cells in their natural environment.
Even though mouse anatomy is very different from human, mouse NK cells still interact with trophoblast cells in the uterus during pregnancy. And the activity of NK cells can influence how dilated the maternal uterine blood vessels become during pregnancy.36 Mice don’t get eclampsia or pre-eclampsia, but the level of blood supply in the uterus can directly affect their reproductive success in other ways. In mice, a high level of blood flow in the uterus can better support larger babies or an increased litter size. For that reason, many scientists think that NK cells help blood flow in a placenta; and that activating these immune cells is a benefit – not a hindrance – to pregnancy. So – even if anatomic details vary – there is evidence that pregnancy and immune-system genes are linked in many species.
If NK cells are there to help – and don’t need to be switched off – where does this leave HLA-G? What does this special HLA protein really do after all? Moffett, Mandelboim – and many others – simply say: we just don’t know.37 But the diversion of studying whether or not HLA-G can switch off NK cells has turned out to not be in vain. An ability of HLA-G to ward off immune cells, even to some extent, led research teams to discover that tumour cells – and perhaps other diseased cells – can usurp HLA-G for their own benefit. That is, some tumours make HLA-G themselves – to shield against an immune cell attack.38 This indicates that HLA-G could, in fact, be a target for anti-tumour drugs – or perhaps used as a diagnostic marker for especially dangerous tumours.39 Another potential medical use for HLA-G is that its ability to inhibit an immune response could be exploited to aid organ transplantation. Time will tell if these clinical applications prove viable.
All this information about trophoblast cells and NK cells in hand – fascinating as it is – doesn’t answer Moffett’s original question of why some women have pre-eclampsia and some don’t. So, after Loke retired in 2002, Moffett decided that an altogether different approach was needed to directly test for the importance of our immune system in pregnancy. She decided to find out whether or not particular immune genes – or combinations of genes between each parent – make pregnancy more or less likely to be successful.
A specific idea about what to look for came to her in thinking through the details of how cells interact in the placenta: on the surface of trophoblast cells, there will be the baby’s HLA-C proteins – which include those inherited from the father. These trophoblast cells contact the mother’s uterine NK cells, and the HLA proteins they have could either weaken or strengthen the activity of the NK cells – depending on how the receptors on the mother’s NK cells react to the versions of HLA-C inherited by the baby. This could influence the level of secretion of growth factors from the NK cells – which impacts blood flow in the placenta, in turn influencing whether or not pregnancy was successful. In this way, Moffett reasoned, the combination of the mother’s NK cell receptor genes and the HLA-C genes inherited by the baby – including those from the father – could affect the success of pregnancy.
Family histories and population-based studies had already indicated that susceptibility to pre-eclampsia could be inherited, but nobody knew which genes were important. Moffett’s idea was nice – but plenty of nice ideas fall by the wayside when tested rigorously. As Darwin’s friend Thomas Huxley said: many a beautiful theory was killed by an ugly fact. To test her idea properly, Moffett had to set up a genetic study to find out if maternal NK cell genes and foetal HLA-C correlate with the success of pregnancy. To do this, genes were analysed in blood taken from 200 women with pre-eclampsia and a similar number of women who had normal pregnancies. Their babies’ genes were analysed using umbilical-cord blood or mouth swabs.
Moffett found that no particular version of HLA-C on its own correlated to whether or not mothers had pre-eclampsia.40 But the risk of pre-eclampsia was increased when certain versions of HLA-C genes were inherited by the baby and the mother had particular NK cell receptor genes. One way that these data can be interpreted is that certain combinations of genes between parents can lead to trophoblast cells switching off NK cells to some extent.41 HLA-C is able to switch off NK cells – as we’ve discussed in the context of ‘missing self’. So HLA proteins inherited by the baby could dampen activity of the mother’s NK cells – depending on the specific versions of HLA-C inherited and which NK-cell receptor genes the mother has. This could lower the NK-cell secretion of growth factors, leading to insufficient blood flow in the placenta and in turn, problems in pregnancy. This is a plausible scenario – consistent with the genetic analysis of parents and babies – but in truth, it’s not really known how these genes influence the frequency of pre-eclampsia. Even without understanding exactly how this works, these results show that differences in our immune-system genes can influence who gets born.
Defects in the placenta can cause other problems in pregnancy, not just pre-eclampsia – for example, recurrent miscarriage. Up to 3 per cent of couples in the UK have three or more consecutive miscarriages, which is more frequent than would be expected by chance – indicating that some couples are prone to miscarry. There are many issues that can underlie recurrent miscarriage, but one involves an insufficient blood flow in the placenta.42 Moffett tested whether or not any particular combination of immune-system genes would be unusually frequent in couples who suffered recurrent miscarriages and discovered that – just like for pre-eclampsia – particular combinations of HLA-C and NK cell receptor genes correlated with the risk.43 This time, her analysis revealed that a receptor protein that increases NK cell activity was protective.44 This is, once again, consistent with the idea that activating uterine NK cells is good for pregnancy.
Moffett also found that poor growth of the baby – a condition formally called foetal growth restriction – similarly correlates with particular combinations of NK receptor genes and HLA-C.45 The genetic link here again fits with the idea that activation of NK cells – and not too much inhibition – is important for a successful pregnancy. Altogether, Moffett’s series of genetic studies indicate that pregnancy is wired to be more successful with couples having particular combinations of immune-system genes.
It’s not that if you have this or that genetic inheritance you must have children with this or that other person, because these effects only slightly increase or decrease the relatively small risk of there being particular problems. As Isaac Asimov said, while thinking about the behaviour of gases: you can’t tell what an individual molecule is going to do, but if you deal with trillions, quadrillions and quintillions, you can tell, very accurately, what they’re going to do on the average.46 Similarly here, these small effects don’t predict who exactly will have problems in pregnancy – but they shape humanity overall.
We are only at the beginning of understanding this, but already there are many implications. First, there are potential medical benefits, as these discoveries seed new ideas for solving problems in fertility and pregnancy. Although it’s not easy to predict which couples are likely to have a problem in pregnancy – because these immune-system genes only contribute a little to the overall risk – it could help to diagnose problems by checking the activity of uterine NK cells during pregnancy. The difficulty with this is in how to assess uterine NK cell activity. NK cells in blood taken from a mother’s arm are obtained more easily than uterine NK cells, but it’s not yet clear whether or not blood cells could report useful information that correlates to the state of cells in the uterus. It’s also not clear – if a problem is detected – how best to manipulate the activity of NK cells in the uterus. Administration of hormones could alter the number of NK cells in the uterus, but we don’t know yet whether or not the number of NK cells, rather than their state of activation, can influence pregnancy outcome.47 Upcoming clinical trials will assess the possibility of using drugs that manipulate NK cells to help with problems in pregnancy.48
Aside from seeding new ideas for medicine, these discoveries say something fundamental about human nature. It could just so happen that reproduction has co-opted use of these highly variable immune-system genes, and we shouldn’t read into it any more than that, in the same way that it doesn’t matter much that the vas deferens tube traffics sperm a longer way round than necessary. But to me, this is not like the vas deferens tube situation and it is almost certain that this does matter; that this genetic link between reproductive success and our ability to fight disease persists because it is beneficial.
There’s not much cost to the vas deferens taking a detour on its way from the testicles to the urethra. So there’s little pressure for the path this tube takes to be as short as possible. In contrast, there’s an immense selective pressure on genes that influence the success of pregnancy or survival from disease, because these processes are so vitally close to what gets inherited; they determine directly who gets born and who lives. All other things being equal, genes that decrease the risk of a mother or baby dying at birth must propagate rapidly in the population.
This would be especially true historically – before medical interventions helped with difficult births. Sadly, even in the twenty-first century, around one in every hundred mothers dies in childbirth in countries where medical provision is poor.49 This gives an estimate of the minimum frequency by which mothers die naturally during or shortly after childbirth. It indicates how strongly genes would be favoured if they could protect – even slightly – against maternal mortality, including those that protect against eclampsia.
Similarly, genes that can provide protection against infectious disease – especially against an illness which can be fatal before having children – must also propagate rapidly in the population (all else being equal). For as long as that disease was prevalent, such a gene or set of genes would rapidly increase in frequency in subsequent generations. Even protection against diseases that are not fatal can still impact the success of one’s children and hence be selected for, through the generations. So variation in immune-system genes across all humanity is certain to be affected by their role in both reproduction and survival from disease.
This plays out as follows: some combinations of compatibility genes will be especially protective against a particular disease, and those versions propagate in the population. But successful pregnancy will have other requirements for variations of these very same genes. Versions of compatibility genes – and other immune-system genes – that favour successful reproduction will also be favoured in subsequent generations. These two pressures on the same sets of genes leads to a balance in what gets selected overall: a balance between versions of these genes that help us survive disease and those that help in pregnancy. In short, the outcome is to keep these genes diverse.
Despite this leap in understanding human nature, Medawar’s paradox remains unsolved: we actually still don’t fully understand how a baby is protected from the mother’s immune system. But, by trying to find the answer, we know that uterine immune cells can help – not hinder – pregnancy. Many genes that regulate pregnancy and birth do not vary much between us. Yet the most variable of all our genes help construct this most intimate of contacts between people.
I suggest that this complex system is in place because no particular set of compatibility genes is perfect. The versions of compatibility genes you have inherited can make you more or less susceptible to various diseases, but there isn’t a version of these genes that optimally protects for all possible diseases. This is likely why pregnancy – and interactions between cells in the placenta in particular – influences which versions of these genes get passed on to the next generation. In effect, the requirements for successful pregnancy help maintain our diversity in compatibility genes.
Without this process in place, one widespread lethal disease can favour particular versions of compatibility genes to be passed on, and cause our variation in these genes to narrow. This would make all of humanity especially susceptible to another disease – one not easily fought with the few compatibility genes left in the population. Admittedly, there’s some fuzziness to how this works in detail, and more research needs to be done. Historians often call physics and mathematics the exact sciences, because biology is always a bit messier (at least for now).
The broad implication of all this is that the compatibility gene connects different aspects of our biology – from pregnancy to immunity – influencing how and when we die in a multitude of ways. Our diversity in these genes weaves a system for immune defence that works in each of us and across all of us. Six decades of exploration from Medawar to Moffett – and countless others in between – show the compatibility gene as our uniqueness and our togetherness.